Buccal, polar and non-polar spray containing zolpidem

ABSTRACT

Buccal aerosol sprays or capsules using polar and non-polar solvents have now been developed which provide zolpidem for rapid absorption through the oral mucosa, resulting in fast onset of effect. The buccal polar compositions of the invention comprise formulation I: aqueous polar solvent, zolpidem, and optional flavoring agent; formulation II: aqueous polar solvent, zolpidem, optionally flavoring agent, and propellant; formulation III: non-polar solvent, zolpidem, and optional flavoring agent; formulation IV: non-polar solvent, zolpidem, optional flavoring agent, and propellant; formulation V: a mixture of a polar solvent and a non-polar solvent, zolpidem, and optional flavoring agent; formulation VI: a mixture of a polar solvent and a non-polar solvent, zolpidem, optional flavoring agent, and propellant.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of application Ser.No. 10/230,060, filed Aug. 29, 2002, pending, which is acontinuation-in-part of application Ser. No. 09/537,118, filed Mar. 29,2000 which is a continuation-in-part of the U.S. national phasedesignation of PCT/US97/17899 filed Oct. 1, 1997, the disclosures ofwhich are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

[0002] It is known that certain biologically active compounds are betterabsorbed through the oral mucosa than through other routes ofadministration, such as through the stomach or intestine. However,formulations suitable for such administration by these latter routespresent their own problems. For example, the biologically activecompound must be compatible with the other components of the compositionsuch as propellants, solvents, etc. Many such formulations have beenproposed. For example, U.S. Pat. No. 4,689,233, Dvorsky et al.,describes a soft gelatin capsule for the administration of theanti-coronary drug nifedipine dissolved in a mixture of polyetheralcohols. U.S. Pat. No. 4,755,389, Jones et al., describes a hardgelatin chewable capsule containing nifedipine. A chewable gelatincapsule containing a solution or dispersion of a drug is described inU.S. Pat. No. 4,935,243, Borkan et al. U.S. Pat. No. 4,919,919, Aouda etal, and U.S. Pat. No. 5,370,862, Klokkers-Bethke, describe anitroglycerin spray for administration to the oral mucosa comprisingnitroglycerin, ethanol, and other components. An orally administeredpump spray is described by Cholcha in U.S. Pat. No. 5,186,925. Aerosolcompositions containing a hydrocarbon propellant and a drug foradministration to a mucosal surface are described in U.K. 2,082,457, Su,U.S. Pat. No. 3,155,574, Silson et al., U.S. Pat. No. 5,011,678, Wang etal., and by Pamell in U.S. Pat. No. 5,128,132. It should be noted thatthese references discuss bioavailability of solutions by inhalationrather than through the membranes to which they are administered.

[0003] Zolpidem is a imidazopyridine having the structure shown below:

[0004] The chemical name for zolpidem is N,N,6-trimethyl-2-p-tolyl-imidazo[1, 2-a]pyridine-3-acetamide

[0005] Zolpidem is a non-benzodiazepine sedative-hypnotic and is used totreat insomnia. To treat insomnia, zolpidem is typically administeredorally at a dose of between 10 and 25 mg. Typically zolpidem isadministered as the tartrate salt, i.e., N,N,6-trimethyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-acetamide L-(+)-tartrate(2:1). Following discontinuation of zolpidem the beneficial effects onsleep can last for up to a week. Tolerance and physical dependence isonly rarely observed with zolpidem. (Goodman and Gilman 's ThePharmacological Basis of Therapeutics, 9^(th) ed., pp. 471-472).

SUMMARY OF THE INVENTION

[0006] A buccal aerosol spray or soft bite gelatin capsule using a polaror non-polar solvent has now been developed which provides biologicallyactive compounds for rapid absorption through the oral mucosa, resultingin fast onset of effect.

[0007] The buccal aerosol spray compositions of the present invention,for transmucosal administration of a pharmacologically active compoundsoluble in a pharmacologically acceptable non-polar solvent comprise inweight % of total composition: pharmaceutically acceptable propellant5-80%, nonpolar solvent 19-85%, active compound 0.05-50%, suitablyadditionally comprising, by weight of total composition a flavoringagent 0.01-10%. Preferably the composition comprises: propellant 10-70%,non-polar solvent 25-89.9%, active compound 0.01-40%, flavoring agent1-8%; most suitably propellant 20-70%, non-polar solvent 25-74.75%,active compound 0.25-35%, flavoring agent 2-7.5%.

[0008] The buccal polar aerosol spray compositions of the presentinvention, for transmucosal administration of a pharmacologically activecompound soluble in a pharmacologically acceptable polar solvent arealso administrable in aerosol form driven by a propellant. In this case,the composition comprises in weight % of total composition: aqueouspolar solvent 10-97%, active compound 0.1-25%, suitably additionallycomprising, by weight of total composition a flavoring agent 0.05-10%and propellant: 2-10%. Preferably the composition comprises: polarsolvent 20-97%, active compound 0.1-15%, flavoring agent 0.1-5% andpropellant 2-5%; most suitably polar solvent 25-97%, active compound0.2-25%, flavoring agent 0.1-2.5% and propellant 2-4%.

[0009] In another embodiment, the buccal polar aerosol spraycompositions of the present invention for transmucosal administration ofa pharmacologically active compound (i.e., those administrable inaerosol form driven by a propellant) comprises a mixture of a polarsolvent and a non-polar solvent comprising in weight % of totalcomposition: solvent 10-97%, active compound 0.05-50%, propellant 5-80%,and optionally a taste mask and/or flavoring agent 0.01-10%. Preferablythe composition comprises: solvent 20-97%, active compound 0.1-40%,propellant 10-70%, and taste mask and/or flavoring agent 1-8%; mostsuitably solvent 25-97%, active compound 0.25-35%, propellant 20-70%,and taste mask and/or flavoring agent 2-7.5%. The ratio of the polarsolvent to the non-polar solvent can range from about 1:99 to about99:1, preferable from about 60:40 to about 40:60, and more preferablyabout 50:50.

[0010] The buccal pump spray composition of the present invention, i.e.,the propellant free composition, for transmucosal administration of apharmacologically active compound wherein said active compound issoluble in a pharmacologically acceptable non-polar solvent comprises inweight % of total composition: non-polar solvent 30-99.69%, activecompound 0.005-55%, and suitably additionally, flavoring agent 0.1-10%.

[0011] The buccal polar pump spray compositions of the presentinvention, i.e., the propellant free composition, for transmucosaladministration of a pharmacologically active compound soluble in apharmacologically acceptable polar solvent comprises in weight % oftotal composition: aqueous polar solvent 30-99.69%, active compound0.001-60%, suitably additionally comprising, by weight of totalcomposition a flavoring agent 0.1-10%. Preferably the compositioncomprises: polar solvent 37-98.58%, active compound 0.005-55%, flavoringagent 0.5-8%; most suitably polar solvent 60.9-97.06%, active compound0.01-40%, flavoring agent 0.75-7.5%.

[0012] In another embodiment, the buccal pump spray composition (i.e.,the propellant free composition) for transmucosal administration of apharmacologically active compound comprises a mixture of a polar solventand a non-polar solvent comprising in weight % of total compositionsolvent 30-99.69%, active compound 0.001-60%, and optionally a tastemask and/or flavoring agent 0.1-10%. Preferably the compositioncomprises: solvent 37-98.58%, active compound 0.005-55%, taste maskand/or flavoring agent 0.5-8%; more preferably the composition comprisessolvent 60.9-97.06%, active compound 0.01-40%, and taste mask and/orflavoring agent 0.75-7.5%. The ratio of the polar solvent to thenon-polar solvent can range from about 1:99 to about 99:1, preferableabout 60:40 to about 40:60, and more preferably about 50:50.

[0013] The soft bite gelatin capsules of the present invention fortransmucosal administration of a pharmacologically active compound, atleast partially soluble in a pharmacologically acceptable non-polarsolvent, having charged thereto a fill composition comprise in weight %of total composition: non-polar solvent 4-99.99%, emulsifier 0-20%,active compound 0.01-80%, provided that said fill composition containsless than 10% of water, suitably additionally comprising, by weight ofthe composition: flavoring agent 0.01-10%. Preferably, the soft bitegelatin capsule comprises: non-polar solvent 21.5-99.975%, emulsifier0-15%, active compound 0.025-70%, flavoring agent 1-8%; most suitably:nonpolar solvent 28.5-97.9%, emulsifier 0-10%, active compound0.1-65.0%, flavoring agent 2-6%.

[0014] The soft bite polar gelatin capsules of the present invention fortransmucosal administration of a pharmacologically active compound, atleast partially soluble in a pharmacologically acceptable polar solvent,having charged thereto a composition comprising in weight % of totalcomposition: polar solvent 25-99.89%, emulsifier 0-20%, active compound0.01-65%, provided that said composition contains less than 10% ofwater, suitably additionally comprising, by weight of the composition:flavoring agent 01-10%. Preferably, the soft bite gelatin capsulecomprises: polar solvent 37-99.95%, emulsifier 0-15%, active compound0.025-55%, flavoring agent 1-8%; most suitably: polar solvent44-96.925%, emulsifier 0-10%, active compound 0.075-50%, flavoring agent2-6%.

[0015] It is an object of the invention to coat the mucosal membraneseither with fine droplets of spray containing the active compounds or asolution or paste thereof from bite capsules.

[0016] It is also an object of the invention to administer to the oralmucosa of a mammalian in need of same, preferably man, by spray or bitecapsule, a predetermined amount of a biologically active compound bythis method or from a soft gelatin capsule.

[0017] A further object is a sealed aerosol spray container containing acomposition of the non polar or polar aerosol spray formulation, and ametered valve suitable for releasing from said container a predeterminedamount of said composition.

[0018] As the propellant evaporates after activation of the aerosolvalve, a mist of fine droplets is formed which contains solvent andactive compound.

[0019] The propellant is a non-Freon material, preferably a C₃₋₈hydrocarbon of a linear or branched configuration. The propellant shouldbe substantially non-aqueous. The propellant produces a pressure in theaerosol container such that under expected normal usage it will producesufficient pressure to expel the solvent from the container when thevalve is activated but not excessive pressure such as to damage thecontainer or valve seals.

[0020] The non-polar solvent is a non-polar hydrocarbon, preferably aC₇₋₁₈ hydrocarbon of a linear or branched configuration, fatty acidesters, and triglycerides such as miglyol. The solvent must dissolve theactive compound and be miscible with the propellant, i.e., solvent andpropellant must form a single phase at a temperature of 0-40° C. apressure range of between 1-3 atm.

[0021] The polar and non-polar aerosol spray compositions of theinvention are intended to be administered from a sealed, pressurizedcontainer. Unlike a pump spray, which allows the entry of air into thecontainer after every activation, the aerosol container of the inventionis sealed at the time of manufacture. The contents of the container arereleased by activation of a metered valve, which does not allow entry ofatmospheric gasses with each activation. Such containers arecommercially available.

[0022] A further object is a pump spray container containing acomposition of the pump spray formulation, and a metered valve suitablefor releasing from said container a predetermined amount of saidcomposition.

[0023] A further object is a soft gelatin bite capsule containing acomposition of as set forth above. The formulation may be in the form ofa viscous solution or paste containing the active compounds. Althoughsolutions are preferred, paste fills may also be used where the activecompound is not soluble or only partially soluble in the solvent ofchoice. Where water is used to form part of the paste composition, itshould not exceed 10% thereof. (All percentages herein are by weightunless otherwise indicated.)

[0024] The polar or non-polar solvent is chosen such that it iscompatible with the gelatin shell and the active compound. The solventpreferably dissolves the active compound. However, other componentswherein the active compound is not soluble or only slightly soluble maybe used and will form a paste fill.

[0025] Soft gelatin capsules are well known in the art. See, forexample, U.S. Pat. No. 4,935,243, Borkan et al., for its teaching ofsuch capsules. The capsules of the present invention are intended to bebitten into to release the low viscosity solution or paste therein,which will then coat the buccal mucosa with the active compounds.Typical capsules, which are swallowed whole or bitten and thenswallowed, deliver the active compounds to the stomach, which results insignificant lag time before maximum blood levels can be achieved orsubject the compound to a large first pass effect. Because of theenhanced absorption of the compounds through the oral mucosa and nochance of a first pass effect, use of the bite capsules of the inventionwill eliminate much of the lag time, resulting in hastened onset ofbiological effect. The shell of a soft gelatin capsule of the inventionmay comprise, for example: gelatin: 50-75%, glycerin 20-30%, colorants0.5-1.5%, water 5-10%, and sorbitol 2-10%.

[0026] The active compound may include, biologically active peptides,central nervous system active amines, sulfonyl ureas, antibiotics,antifungals, antivirals, sleep inducers, antiasthmatics, bronchialdilators, antiemetics, histamine H-2 receptor antagonists, barbiturates,prostaglandins and neutraceuticals.

[0027] The active compounds may also include antihistamines, alkaloids,hormones, benzodiazepines and narcotic analgesics. While not limitedthereto, these active compounds are particularly suitable for non-polarpump spray formulation and application.

[0028] The active compounds may also include p-FOX (fatty acidoxidation) inhibitors, acetylcholinesterase inhibitors, nerve impulseinhibitors, anti-cholinergics, anti-convulsants, anti-psychotics,anxiolytic agents, dopamine metabolism inhibitors, agents to treat poststroke sequelae, neuroprotectants, agents to treat Alzheimer's disease,neurotransmitters, neurotransmitter agonists, sedatives, agents fortreating attention deficit disorder, agents for treating narcolepsy,central adregenic antagonists, anti-depression agents, agents fortreating Parkinson's disease, benzodiazepine antagonists, stimulants,neurotransmitter antagonists, tranquilizers, or a mixture thereof.

[0029] In one embodiment, the active compound is zolpidem or apharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWING

[0030]FIG. 1. is a schematic diagram showing routes of absorption andprocessing of pharmacologically active substances in a mammalian system.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The preferred active compounds of the present invention are in anionized, salt form or as the free base of the pharmaceuticallyacceptable salts thereof (provided, for the aerosol or pump spraycompositions, they are soluble in the spray solvent). These compoundsare soluble in the non-polar solvents of the invention at usefulconcentrations or can be prepared as pastes at useful concentrations.These concentrations may be less than the standard accepted dose forthese compounds since there is enhanced absorption of the compoundsthrough the oral mucosa. This aspect of the invention is especiallyimportant when there is a large (40-99.99%) first pass effect.

[0032] As propellants for the non polar sprays, propane, N-butane,iso-butane, N-pentane, iso-pentane, and neo-pentane, and mixturesthereof may be used. N-butane and iso-butane, as single gases, are thepreferred propellants. It is permissible for the propellant to have awater content of no more than 0.2%, typically 0.1-0.2%. All percentagesherein are by weight unless otherwise indicated. It is also preferablethat the propellant be synthetically produced to minimize the presenceof contaminants which are harmful to the active compounds. Thesecontaminants include oxidizing agents, reducing agents, Lewis acids orbases, and water. The concentration of each of these should be less than0.1%, except that water may be as high as 0.2%.

[0033] Suitable non-polar solvents for the capsules and the non-polarsprays include (C₂-C₂₄) fatty acid (C₂-C₆) esters, C₇-C₁₈ hydrocarbon,C₂-C₆ alkanoyl esters, and the triglycerides of the corresponding acids.When the capsule fill is a paste, other liquid components may be usedinstead of the above low molecular weight solvents. These include soyaoil, corn oil, other vegetable oils.

[0034] As solvents for the polar capsules or sprays there may be usedlow molecular weight polyethyleneglycols (PEG) of 400-1000 Mw(preferably 400-600), low molecular weight (C₂-C₈) mono and polyols andalcohols of C₇-C₁₈ linear or branch chain hydrocarbons, glycerin mayalso be present and water may also be used in the sprays, but only inlimited amount in the capsules.

[0035] It is expected that some glycerin and water used to make thegelatin shell will migrate from the shell to the fill during the curingof the shell. Likewise, there may be some migration of components fromthe fill to the shell during curing and even throughout the shelf-lifeof the capsule.

[0036] Therefore, the values given herein are for the compositions asprepared, it being within the scope of the invention that minorvariations will occur.

[0037] The preferred flavoring agents are synthetic or natural oil ofpeppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners(sugars, aspartame, saccharin, etc.), and combinations thereof.

[0038] The compositions may further include a taste mask. The term“taste mask” as used herein means an agent that can hide or minimize anundesirable flavor such as a bitter or sour flavor. A representativetaste mask is a combination of vanillin, ethyl vanillin, maltol,iso-amyl acetate, ethyl oxyhydrate, anisic aldehyde, and propyleneglycol (commercially available as “PFC 9885 Bitter Mask” fromPharmaceutical Flavor Clinic of Camden, N.J.). A taste mask incombination with a flavoring agent is particularly advantageous when theactive compound is an alkaloid since alkaloids often have a bittertaste.

[0039] The active substances include the active compounds selected fromthe group consisting of cyclosporine, sermorelin, octreotide acetate,calcitonin-salmon, insulin lispro, sumatriptan succinate, clozepine,cyclobenzaprine, dexfenfluramine hydrochloride, glyburide, zidovudine,erythromycin, ciprofloxacin, ondansetron hydrochloride, dimenhydrinate,cimetidine hydrochloride, famotidine, phenyloin sodium, phenyloin,carboprost thromethamine, carboprost, diphenhydramine hydrochloride,isoproterenol hydrochloride, terbutaline sulfate, terbutaline,theophylline, albuterol sulfate and neutraceuticals, that is to saynutrients with pharmacological action such as but not limited tocamitine, valerian, echinacea, and the like.

[0040] In another embodiment, the active compound is a p-FOX (fatty acidoxidation) inhibitor, acetylcholinesterase inhibitor, nerve impulseinhibitor, anti-cholinergic, anti-convulsant, anti-psychotic, anxiolyticagent, dopamine metabolism inhibitor, agent to treat post strokesequelae, neuroprotectant, agent to treat Alzheimer's disease,neurotransmitter, neurotransmitter agonist, sedative, agent for treatingattention deficit disorder, agent for treating narcolepsy, centraladregenic antagonist, anti-depression agent, agent for treatingParkinson's disease, benzodiazepine antagonist, stimulant,neurotransmitter antagonist, tranquilizer, or a mixture thereof.

[0041] In one embodiment the active compound is a p-FOX inhibitor. Asuitable p-FOX inhibitor for use in the buccal sprays of the inventionincludes, but is not limited to, ranolazine.

[0042] In one embodiment the active compound is an acetylcholinesteraseinhibitor. Suitable acetylcholinesterase inhibitors for use in thebuccal sprays of the invention include, but are not limited to,galantamine, neostigmine, physostigmine, and edrophonium.

[0043] In one embodiment the active compound is a nerve impulseinhibitor. Suitable nerve impulse inhibitors for use in the buccalsprays of the invention include, but are not limited to,levobupivacaine, lidocaine, prilocalne, mepivacaine, propofol,rapacuronium bromide, ropivacaine, tubocurarine, atracurium, doxaurium,mivacurium, pancuronium, vercuronium, pipecuronium, and rocuronium.

[0044] In one embodiment the active compound is an anti-cholinergic.Suitable anti-cholinergics for use in the buccal sprays of the inventioninclude, but are not limited to, amantadine, ipratropium, oxitropium,and dicycloverine.

[0045] In one embodiment the active compound is an anti-convulsant.Suitable anti-convulsants for use in the buccal sprays of the inventioninclude, but are not limited to, acetazolamide, carbamazepine,clonazepam, diazepam, divalproex (valproic acid), ethosuximide,lamotrignine acid, levetriacetam, oxcarbazepine, phenobarbital,phenyloin, pregabalin, primidone, remacemide, trimethadione, topiramate,vigabatrin, and zonisamide.

[0046] In one embodiment the active compound is an anti-psychotic.Suitable anti-psychotics for use in the buccal sprays of the inventioninclude, but are not limited to, amisulpride, aripiprazole bifemelane,bromperidol, clozapine, chlorpromazine, haloperidol, iloperidoneloperidone, olanzapine, quetiapine, fluphenazine, fumarate, risperidone,thiothixene, thioridazine, sulpride, and ziprasidone,

[0047] In one embodiment the active compound is an anxiolytic agent.Suitable anxiolytic agents for use in the buccal sprays of the inventioninclude, but are not limited to, amitryptiline, atracurium, buspirone,chlorzoxazone, clorazepate, cisatracurium, cyclobenzaprine, eperisone,esopiclone, hydroxyzine, mirtazapine, mivacurium, pagoclone, sulperide,zaleplon, and zopiclone.

[0048] In one embodiment the active compound is a dopamine metabolisminhibitor. Suitable dopamine metabolism inhibitors for use in the buccalsprays of the invention include, but are not limited to, entacapone,lazebemide, selegiline, and tolcapone.

[0049] In one embodiment the active compound is an agent to treat poststroke sequelae. Suitable agents to treat post stroke sequelae for usein the buccal sprays of the invention include, but are not limited to,glatiramer, interferon beta 1A, interferon beta 1B, estradiol, andprogesterone.

[0050] In one embodiment the active compound is a neuroprotectant.Suitable neuroprotectants for use in the buccal sprays of the inventioninclude, but are not limited to, donepezil, memanine, nimodipine,riluzole, rivastigmine, tacrine, TAK147, and xaliproden.

[0051] In one embodiment the active compound is an agent to treatAlzheimer's disease. Suitable agents to treat Alzheimer's disease foruse in the buccal sprays of the invention include, but are not limitedto, carbidopa, levodopa, tacrine, donezepil, rivastigmine, andgalantamine.

[0052] In one embodiment the active compound is a neurotransmitter.Suitable neurotransmitters for use in the buccal sprays of the inventioninclude, but are not limited to, acetylcholine, serotonin,5-hydroxytryptamine (5-HT), GABA, glutamate, aspartate, glycine,histamine, epinephrine, norpinephrine, dopamine, adenosine, ATP, andnitric oxide.

[0053] In one embodiment the active compound is a neurotransmitteragonist. Suitable neurotransmitter agonists for use in the buccal spraysof the invention include, but are not limited to, almotriptan,aniracetam, atomoxetine, benserazide, bromocriptine, bupropion,cabergoline, citalopram, clomipramine, desipramine, diazepam,dihydroergotamine, doxepin duloxetine, eletriptan, escitalopram,fluvoxamine, gabapentin, imipramine, moclobemide, naratriptan,nefazodone, nefiracetam acamprosate, nicergoline, nortryptiline,paroxetine, pergolide, pramipexole, rizatriptan, ropinirole, sertraline,sibutramine, sumatriptan, tiagabine, trazodone, venlafaxine, andzolmitriptan.

[0054] In one embodiment the active compound is a sedative. Suitablesedatives for use in the buccal sprays of the invention include, but arenot limited to, dexmedetomidine, eszopiclone, indiplon, zolpidem, andzaleplon.

[0055] In one embodiment the active compound is an agent for treatingattention deficit disorder. Suitable agents for treating attentiondeficit disorder for use in the buccal sprays of the invention include,but are not limited to, amphetamine, dextroamphetamine, methylphenidate,and pemoline.

[0056] In one embodiment the active compound is an agent for treatingnarcolepsy. Suitable agents for treating narcolepsy for use in thebuccal sprays of the invention include, but are not limited to,modafinil and mazindol.

[0057] In one embodiment the active compound is a central adregenicantagonists. A suitable central adregenic antagonists for use in thebuccal sprays of the invention includes, but is not limited to,mesoridazine.

[0058] In one embodiment the active compound is an anti-depressionagent. Suitable anti-depression agents for use in the buccal sprays ofthe invention include, but are not limited to, amitriptyline, amoxapine,bupropion, clomipramine, clomipramine, clorgyline, desipramine, doxepin,fluoxetine, imipramine, isocarboxazid, maprotiline, mirtazapine,nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline,sertraline, tranylcypromine, trazodone, and venlafaxine.

[0059] In one embodiment the active compound is an agent for treatingParkinson's disease. Suitable agents for treating Parkinson's diseasefor use in the buccal sprays of the invention include, but are notlimited to, amantadine, bromocriptine, carvidopa, levodopa, pergolide,and selegiline.

[0060] In one embodiment the active compound is a benzodiazepineantagonist. A suitable benzodiazepine antagonist for use in the buccalsprays of the invention includes, but is not limited to, flumazenil.

[0061] In one embodiment the active compound is a neurotransmitterantagonist. A suitable neurotransmitter antagonist for use in the buccalsprays of the invention includes, but is not limited, to deramciclane.

[0062] In one embodiment the active compound is a stimulant. Suitablestimulants for use in the buccal sprays of the invention include, butare not limited to, amphetamine, dextroamphetamine, dinoprostone,methylphenidate, methylphenidate, modafinil, and pemoline.

[0063] In one embodiment the active compound is a tranquilizer. Asuitable tranquilizer for use in the buccal sprays of the inventionincludes, but is not limited to, mesoridazine.

[0064] In a another embodiment, the active compound is zolpidem or apharmaceutically acceptable salt thereof. In one embodiment, the activecompound is zolpidem tartrate.

[0065] Typically, when zolpidem or a pharmaceutically acceptable saltthereof is the active compound the buccal spray contains from about 0.01to 20 weight/weight (w/w) percent zolpidem, more preferably 0.1 to 15w/w percent zolpidem, and most preferably 0.2 to 10 w/w percentzolpidem.

[0066] The invention further relates to a method of treating insomnia ina patient by spraying the oral mucosa of the patient with atherapeutically effective amount of a buccal spray comprising zolpidemor a pharmaceutically acceptable salt thereof.

[0067] The formulations of the present invention comprise an activecompound or a pharmaceutically acceptable salt thereof. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids or bases including organicand inorganic acids or bases.

[0068] When an active compound of the present invention is acidic, saltsmay be prepared from pharmaceutically acceptable non-toxic bases. Saltsderived from all stable forms of inorganic bases include aluminum,ammonium, calcium, copper, iron, lithium, magnesium, manganese,potassium, sodium, zinc, etc. Particularly preferred are the ammonium,calcium, magnesium, potassium, and sodium salts. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basicion-exchange resins such as arginine, betaine, caffeine, choline, N,Ndibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,isopropylamine, lysine, methyl-glucosamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purine, theobromine,triethylamine, trimethylamine, tripropylamine, etc.

[0069] When an active compound of the present invention is basic, saltsmay be prepared from pharmaceutically acceptable non-toxic acids. Suchacids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethane-sulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, mandelic, methanesulfonic, mucic, nitric,pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic, etc. Particularly preferred are citric, hydrobromic,maleic, phosphoric, sulfuric, and tartaric acids.

[0070] In the discussion of methods of treatment herein, reference tothe active compounds is meant to also include the pharmaceuticallyacceptable salts thereof. While certain formulations are set forthherein, the actual amounts to be administered to the mammal or man inneed of same are to be determined by the treating physician.

[0071] The invention is further defined by reference to the followingexamples, which are intended to be illustrative and not limiting.

[0072] The following are examples of certain classes. All values unlessotherwise specified are in weight percent.

EXAMPLES Example 1 Biologically Active Peptides Including PeptideHormones

[0073] A. Cyclosporine Lingual Spray most Amounts preferred amountpreferred amount cyclosporine  5-50 10-35 15-25 water  5-20 7.5-50 9.5-12  ethanol  5-60 7.5-50  10-20 polyethylene glycol 20-60 30-4535-40 flavors 0.1-5   1-4 2-3

[0074] B. Cyclosporine Non-Polar Lingual Spray most preferred Amountspreferred amount amount cyclosporine  1-50  3-40  5-30 Migylol 20 2530-40 Polyoxyethylated castor 20 25 30-40 oil Butane 25-80 30-70 33-50flavors 0.1-5   1-4 2-3

[0075] C. Cyclosporine Non-Polar Bite Capsule Amounts preferred amountmost preferred amount cyclosporine  1-35  5-25 10-20 olive oil 25-6035-55 30-45 polyoxyethylated 25-60 35-55 30-45 oleic glycerides flavors0.1-5   1-4 2-3

[0076] D. Cyclosporine Bite Capsule Amounts preferred amount mostpreferred amount cyclosporine  5-50 10-35 15-25 polyethylene 20-60 30-4535-40 glycol glycerin  5-30 7.5-25  10-20 propylene glycol  5-30 7.5-25 10-20 flavors 0.1-10  1-8 3-6

[0077] E. Sermorelin (as the Acetate) Lingual Spray most Amountspreferred amount preferred sermorelin (as the acetate) .01-5   .1-3  .2-1.0 mannitol  1-25  5-20 10-15 monobasic sodium phosphate, 0.1-5   1-31  .5-2.5 dibasic sodium phosphate 0.01-5   .05-3   0.1-0.5 waterethanol  5-30 7.5-25  9.5-15  polyethylene glycol 20-60 30-45 35-40propylene glycol  5-25 10-20 12-17 flavors 0.1-5   1-4 2-3

[0078] F. Octreotide Acetate (Sandostatin) Lingual Spray Amountspreferred amount most preferred amount octreotide 0.001-0.5  0.005-0.250 0.01-0.10 acetate acetic acid  1-10 2-8 4-6 sodium acetate 1-10 2-8 4-6 sodium  3-30  .5-25  15-20 chloride flavors 0.1-5  0.5-.4  2-3 ethanol  5-30 7.5-20  9.5-15  water 15-95 35-90 65-85flavors 0.1-5   1-4 2-3

[0079] G. Calcitonin-Salmon Lingual Spray Amounts preferred amount mostpreferred amount calcitonin- 0.001-5    0.005-2     01-1.5 salmonethanol  2-15  3-10   7-9.5 water 30-95 50-90 60-80 polyethylene  2-15 3-10   7-9.5 glycol sodium 2.5-20   5-15   10-12.5 chloride flavors0.1-5   1-4 2-3

[0080] H. Insulin Lispro, Lingual Spray preferred most Amounts amountpreferred amount insulin 20-60  4-55  5-50 glycerin 0.1-10  0.25-5  0.1-1.5 dibasic sodium  1-15 2.5-10  4-8 phosphate m-cresol,  1-25  5-25 7.5-12.5 zinc oxide 0.01-0.25  .05-0.15 0.075-0.10  m-cresol 0.1-1  0.2-0.8 0.4-0.6 phenol trace amounts trace amounts trace amounts ethanol 5-20 7.5-15   9-12 water 30-90 40-80 50-75 propylene glycol  5-207.5-15   9-12 flavors 0.1-5   0.5-3   0.75-2  

Example 2 CNS Active Amines and their Salts: Including but not Limitedto Tricyclic Amines, GABA Analogues, Thiazides, PhenothiazineDerivatives, Serotonin Antagonists and Serotonin Reuptake Inhibitors

[0081] A. Sumatriptan Succinate Lingual Spray most Amounts preferredamount preferred amount sumatriptan succinate 0.5-30   1-20 10-15ethanol  5-60 7.5-50  10-20 propylene glycol  5-30 7.5-20  10-15polyethylene glycol  0-60 30-45 35-40 water  5-30 7.5-20  10-15 flavors0.1-5   1-4 2-3

[0082] B. Sumatriptan Succinate Bite Capsule most Amounts preferredamount preferred amount sumatriptan succinate 0.01-5   0.05-3.5 0.075-1.75  polyethylene glycol 25-70 30-60 35-50 glycerin 25-70 30-6035-50 flavors 0.1-10  1-8 3-6

[0083] C. Clozepine Lingual Spray Amounts preferred amount mostpreferred amount clozepine 0.5-30   1-20 10-15 ethanol  5-60 7.5-50 10-20 propylene glycol  5-30 7.5-20  10-15 polyethylene  0-60 30-4535-40 glycol water  5-30 7.5-20  10-15 flavors 0.1-5   1-4 2-3

[0084] D. Clozepine Non-Polar Lingual Spray with Propellant preferredmost preferred Amounts amount amount clozepine 0.5-30   1-20 10-15Migylol 20-85 25-70 30-40 Butanol  5-80 30-75 60-70 flavors 0.1-5   1-42-3

[0085] E. Clozepine Non-Polar Lingual Spray without Propellant Amountspreferred amount most preferred amount clozepine 0.5-30   1-20 10-15Migylol   70-99.5 80-99 85-90 flavors 0.1-5   1-4 2-3

[0086] F. Cyclobenzaprine Non-Polar Lingual Spray most Amounts preferredamount preferred amount cyclobenzaprine (base) 0.5-30   1-20 10-15Migylol 20-85 25-70 30-40 Iso-butane 15-80 30-75 60-70 flavors 0.1-5  1-4 2-3

[0087] G. Dexfenfluramine Hydrochloride Lingual Spray Amounts preferredamount most preferred amount dexfenfluramine  5-30 7.5-20  10-15 Hclethanol  5-60 7.5-50  10-20 propylene glycol  5-30 7.5-20  10-15polyethylene  0-60 30-45 35-40 glycol water  5-30 7.5-20  10-15 flavors0.1-5   1-4 2-3

Example 3 Sulfonylureas

[0088] A. Glyburide Lingual Spray Amounts preferred amount mostpreferred amount glyburide 0.25-25   0.5-20  0.75-15   ethanol  5-60−7.5-50    10-20 propylene glycol  5-30 7.5-20  10-15 polyethylene  0-6030-45 35-40 glycol water 2.5-30   5-20  6-15 flavors 0.1-5   1-4 2-3

[0089] B. Glyburide Non-Polar Bite Capsule most Amounts preferred amountpreferred amount glyburide 0.01-10   0.025-7.5  0.1-4   olive oil 30-6035-55 30-50 polyoxyethylated oleic 30-60 35-55 30-50 glycerides flavors0.1-5   1-4 2-3

Example 4 Antibiotics Anti-Fungals and Anti-Virals

[0090] A. Zidovudine [formerly called azidothymidine (AZT) (Retrovir)]Non-Polar Lingual Spray Amounts preferred amount most preferred amountzidovudine 10-50 15-40 25-35 Soya oil 20-85 25-70 30-40 Butane 15-8030-75 60-70 flavors 0.1-5   1-4 2-3

[0091] B. Erythromycin Bite Capsule Bite Capsule Amounts preferredamount most preferred amount erythromycin 25-65 30-50 35-45polyoxyethylene  5-70 30-60 45-55 glycol glycerin  5-20 7.5-15   10-12.5 flavors  1-10 2-8 3-6

[0092] C. Ciprofloxacin Hydrochloride Bite Capsule most Amountspreferred amount preferred amount ciprofloxacin 25-65 35-55 40-50hydrochloride glycerin  5-20 7.5-15    10-12.5 polyethylene glycol120-75  30-65 40-60 flavors  1-10 2-8 3-6

[0093] D. Zidovudine [Formerly Called Azidothymidine (AZT) (Retrovir)]Lingual Spray Amounts preferred amount most preferred amount zidovudine10-50 15-40 25-35 water 30-80 40-75 45-70 ethanol  5-20 7.5-15  9.5-12.5 polyethylene  5-20 7.5-15   9.5-12.5 glycol flavors 0.1-5  1-4 2-3

Example 5 Anti-Emetics

[0094] A. Ondansetron Hydrochloride Lingual Spray preferred mostpreferred Amounts amount amount ondansetron hydrochloride  1-25  2-202.5-15  citric acid monohydrate  1-10 2-8 2.5-5   sodium citratedihydrate 0.5-5   1-4 1.25-2.5  water  1-90  5-85 10-75 ethanol  5-307.5-20  9.5-15  propylene glycol  5-30 7.5-20  9.5-15  polyethyleneglycol  5-30 7.5-20  9.5-15  flavors  1-10 3-8   5-7.5

[0095] B. Dimenhydrinate Bite Capsule Amounts preferred amount mostpreferred amount dimenhydrinate 0.5-30   2-25  3-15 glycerin  5-207.5-15    10-12.5 polyethylene 45-95 50-90 55-85 glycol flavors  1-102-8 3-6

[0096] C. Dimenhydrinate Polar Lingual Spray most Amounts preferredamount preferred amount dimenhydrinate  3-50  4-40  5-35 water  5-9010-80 15-75 ethanol  1-80  3-50  5-10 polyethylene glycol  1-80  3-50 5-15 sorbitol 0.1-5   0.2-40  0.4-1.0 aspartame 0.01-0.5  0.02-0.4 0.04-0.1  flavors 0.1-5   1-4 2-3

Example 6

[0097] Amounts preferred amount most preferred amount cimetidine HCl10-60 15-55 25-50 glycerin  5-20 7.5-15    10-12.5 polyethylene 20-9025-85  30-75 glycol flavors  1-10 2-8 3-6

[0098] B. Famotidine Lingual Spray Amounts preferred amount mostpreferred amount famotidine  1-35  5-30  7-20 water 2.5-25   3-20  5-10L-aspartic acid 0.1-20   1-15  5-10 polyethylene 20-97 30-95 50-85glycol flavors 0.1-10    1-7.5 2-5

[0099] C. Famotidine Non-Polar Lingual Spray Amounts preferred amountmost preferred amount famotidine  1-35  5-30  7-20 Soya oil 10-50 15-4015-20 Butane1  5-80 30-75 45-70 polyoxyethylated 10-50 15-40 15-20 oleicglycerides flavors 0.1-5   1-4 2-3

Example 7 Barbiturates

[0100] A. Phenytoin Sodium Lingual Spray Amounts preferred amount mostpreferred amount phenytoin sodium 10-60 15-55 20-40 water 2.5-25   3-20 5-10 ethanol  5-30 7.5-20  9.5-15  propylene glycol  5-30 7.5-20 9.5-15  polyethylene  5-30 7.5-20  9.5-15  glycol flavors  1-10 3-8  5-7.5

[0101] B. Phenytoin Non-Polar Lingual Spray most Amounts preferredamount preferred amount phenytoin  5-45 10-40 15-35 migylol 10-50 15-4015-20 Butane 15-80 30-75 60-70 polyoxyethylated 10-50 15-40 15-20 oleicglycerides flavors 0.1-10  1-8   5-7.5

Example 8 Prostaglandins

[0102] A. Carboprost Thromethamine Lingual Spray preferred most Amountsamount preferred amount carboprost thromethamine 0.05-5   0.1-3  0.25-2.5  water 50-95 60-80 65-75 ethanol  5-20 7.5-15   9.5-12.5polyethylene glycol  5-20 7.5-15   9.5-12.5 sodium chloride  1-20  3-154-8 flavors 0.1-5   1-4 2-3

[0103] pH is adjusted with sodium hydroxide and/or hydrochloric acid

[0104] B. Carboprost Non-Polar Lingual Spray most Amounts preferredamount preferred amount carboprost 0.05-5   0.1-3   0.25-2.5  migylol25-50 30-45 35-40 Butane  5-60 10-50 20-35 polyoxyethylated 25-50 30-4535-40 oleic glycerides flavors 0.1-10  1-8   5-7.5

Example 9 Neutraceuticals

[0105] A. Carnitine as Bite Capsule (Contents are a Paste) most Amountspreferred amount preferred amount carnitine fumarate  6-80 30-70 45-65soya oil 7.5-50  10-40 12.5-35   soya lecithin 0.001-1.0  0.005-0.5 .01-0.1 Soya fats 7.5-50  10-40 12.5-35   flavors  1-10 2-8 3-6

[0106] B. Valerian as Lingual Spray Amounts preferred amount mostpreferred amount valerian extract 0.1-10  0.2-7   0.25-5   water 50-9560-80 65-75 ethanol  5-20 7.5-15   9.5-12.5 polyethylene  5-20 7.5-15  9.5-12.5 glycol flavors  1-10 2-8 3-6

[0107] C. Echinacea as Bite Capsule most Amounts preferred amountpreferred amount echinacea extract 30-85 40-75 45-55 soya oil 7.5-50 10-40 12.5-35   soya lecithin 0.001-1.0  0.005-0.5  .01-0.1 Soya fats7.5-50  10-40 12.5-35   flavors  1-10 2-8 3-6

[0108] D. Mixtures of Ingredients Amounts preferred amount mostpreferred amount magnesium oxide 15-40 20-35 25-30 chromium 0.01-1.0 0.02-0.5  .025-0.75 picolinate folic acid .025-3.0  0.05-2.0  0.25-0.5 vitamin B-12 0.01-1.0  0.02-0.5  .025-0.75 vitamin E 15-40 20-35 25-30Soya oil 10-40 12.5-35   15-20 soya lecithin 0.1-5   0.2-4   0.5-1.5soya fat 10-40 15-35 17.5-20  

Example 10 Sleep Inducers (also CNS active amine)

[0109] A. Diphenhydramine Hydrochloride Lingual Spray Amounts preferredamount most preferred amount diphenhydramine   3-50.  4-40  5-35 HClwater  5-90 10-80 50-75 ethanol  1-80  3-50  5-10 polyethylene  1-80 3-50  5-15 glycol Sorbitol 0.1-5   0.2-4   0.4-1.0 aspartame 0.01-0.5 0.02-0.4  0.04-0.1  flavors 0.1-5   1-4 2-3

Example 11 Anti-Asthmatics-Bronchodilators

[0110] A. Isoproterenol Hydrochloride as Polar Lingual Spray mostAmounts preferred amount preferred amount isoproterenol 0.1-10  0.2-7.50.5-6   Hydrochloride water  5-90 10-80 50-75 ethanol  1-80  3-50  5-10polyethylene glycol  1-80  3-50  5-15 Sorbitol 0.1-5   0.2-4   0.4-1.0aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5   1-4 2-3

[0111] B. Terbutaline Sulfate as Polar Lingual Spray Amounts preferredamount most preferred amount terbutaline sulfate 0.1-10  0.2-7.5 0.5-6  water  5-90 10-80 50-75 ethanol  1-10 2-8 2.5-5   Sorbitol 0.1-5  0.2-4   0.4-1.0 aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5  1-4 2-3

[0112] C. Terbutaline as Non-Polar Lingual Spray most preferred Amountspreferred amount amount terbutaline 0.1-10  0.2-7.5 0.5-6   migylol25-50 30-45 35-40 isobutane  5-60 10-50 20-35 polyoxyethylated 25-5030-45 35-40 oleic glycerides flavors 0.1-10  1-8   5-7.5

[0113] D. Theophylline Polar Bite Capsule Amounts preferred amount mostpreferred amount theophylline  5-50 10-40 15-30 polyethylene 20-60 25-5030-40 glycol glycerin 25-50 35-45 30-40 propylene glycol 25-50 35-4530-40 flavors 0.1-5   1-4 2-3

[0114] E. Albuterol Sulfate as Polar Lingual Spray Amounts preferredamount most preferred amount albuterol sulfate 0.1-10  0.2-7.5  0.5-6  water  5-90 10-80 50-75 ethanol  1-10 2-8 2.5-5   Sorbitol 0.1-5  0.2-4   0.4-1.0 aspartame 0.01-0.5  0.02-0.4  0.04-0.1  flavors 0.1-5  1-4 2-3

Example 12 Polar Solvent Formulations Using a Propellant

[0115] A. Sulfonylurea Preferred Amount Amount Most-Preferred Amountglyburide 0.1-25%  0.5-15%  0.6-10%  Ethanol 40-99% 60-97% 70-97% Water0.01-5%   0.1-4%   0.2-2%   Flavors 0.05-10%   0.1-5%   0.1-2.5%Propellant  2-10% 3-5% 3-4%

[0116] B. Prostaglandin E (Vasodilator) Most- Amount Preferred AmountPreferred Amount prostaglandin E₁ 0.01-10%   0.1-5%   0.2-3%   Ethanol10-90% 20-75% 25-50% Propylene glycol  1-90%  5-80% 10-75% Water0.01-5%   0.1-4%   0.2-2%   Flavors 0.05-10%   0.1-5%   0.1-2.5%Propellant  2-10% 3-5% 3-4%

[0117] C. Promethazine (Antiemetic, Sleep Inducer, and CNS Active Amine)Most- Amount Preferred Amount Preferred Amount promethazine  1-25% 3-15%  5-12% Ethanol 10-90% 20-75% 25-50% Propylene glycol  1-90% 5-80% 10-75% Water 0.01-5%   0.1-4%   0.2-2%   Flavors 0.05-10%  0.1-5%   0.1-2.5% Propellant  2-10% 3-5% 3-4%

[0118] D. Meclizine Most- Amount Preferred Amount Preferred Amountmeclizine  1-25%  3-15%  5-12% Ethanol  1-15%  2-10% 3-6  Propyleneglycol 20-98%  5-90% 10-85% Water 0.01-5%   0.1-4%   0.2-2%   Flavors0.05-10%   0.1-5%   0.1-2.5% Propellant  2-10% 3-5% 3-4%

Example 13 Zolpidem Formulations

[0119] A. A propellant free zolpidem formulation containing a polarsolvent has the following formula: Component Percent (w/w) Zolpidemtartrate 2.5 Propylene glycol 15 Glycerol 10 Bitter mask 0.2Benzalkonium chloride 0.1 Citrate buffer (1N, pH 6) 8 Ethanol QS 100 mL

[0120] B. A zolpidem formulation in a polar solvent with a propellanthas the following formula: Component Percent (w/w) Zolpidem tartrate 2.5Ethanol 35 Glycerol 10 Bitter mask 0.2 Butane QS 100

[0121] C. A propellant free zolpidem formulation in a mixture of a polarand a non-polar solvent has the following formula: Component Percent(w/w) Zolpidem tartrate 0.5 Miglyol 15 Lemon oil 10 Ethanol QS to 100 mL

[0122] D. A zolpidem formulation in a mixture of a polar solvent and anon-polar solvent with a propellant can be made according to thefollowing formula: Component Percent (w/w) Zolpidem tartrate 0.5 Liquidparaffin 15 Lemon oil 10 Ethanol 40 Butane QS 100

[0123] E. A propellant free zolpidem formulation in a non-polar solventcan be made according to the following formula: Component Percent (w/w)Zolpidem Tartrate 0.2 Lemon oil 0.1 Miglyol Qs to 100

[0124] F. A zolpidem formulation in a non-polar solvent with apropellant can be made according to the following formula: ComponentPercent (w/w) Zolpidem Tartrate 0.2 Lemon oil 0.1 Miglyol 50 Butane Qsto

What is claimed is:
 1. A propellant free buccal spray composition fortransmucosal administration of zolpidem or a pharmaceutically acceptablesalt thereof comprising: zolpidem or a pharmaceutically acceptable saltthereof in an amount of between 0.001 and 60 percent by weight of thetotal composition; and a polar solvent in an amount between 30 and 99percent by weight of the total composition.
 2. The composition of claim1, further comprising a taste mask and/or flavoring agent in an amountof between 0.1 and 10 percent by weight of the total composition.
 3. Thecomposition of claim 2, wherein the polar solvent is present in anamount between 37 and 98 percent by weight of the total composition, thezolpidem or a pharmaceutically acceptable salt thereof is present in anamount between 0.005 and 55 percent by weight of the total composition,and the taste mask and/or flavoring agent is present in an amountbetween 0.5 and 8 percent by weight of the total composition.
 4. Thecomposition of claim 3, wherein the polar solvent is present in anamount between 60 and 97 percent by weight of the total composition, thezolpidem or a pharmaceutically acceptable salt thereof is present in anamount between 0.01 and 40 percent by weight of the total composition,and the taste mask and/or flavoring agent is present in an amountbetween 0.75 and 7.5 percent by weight of the total composition.
 5. Thecomposition of claim 1, wherein the polar solvent is selected from thegroup consisting of polyethylene glycols having a molecular weightbetween 400 and 1000, C₂ to C₈ mono- and poly-alcohols, and C₇ to C₁₈alcohols of linear or branched configuration.
 6. The composition ofclaim 1, wherein the polar solvent comprises polyethylene glycol.
 7. Thecomposition of claim 1, wherein the polar solvent comprises ethanol. 8.The composition of claim 2, wherein the flavoring agent is selected fromthe group consisting of synthetic or natural oil of peppermint, oil ofspearmint, citrus oil, fruit flavors, sweeteners, and mixtures thereof.9. A method of administering zolpidem or a pharmaceutically acceptablesalt thereof to a mammal, comprising spraying the oral mucosa of themammal with the composition of claim
 1. 10. The method of claim 9,wherein the amount of the spray is predetermined.
 11. A buccal spraycomposition for transmucosal administration of zolpidem or apharmaceutically acceptable salt thereof comprising: zolpidem or apharmaceutically acceptable salt thereof in an amount of between 0.1 and25 percent by weight of the total composition; a polar solvent in anamount between 10 and 97 percent by weight of the total composition; anda propellant in an amount between 2 and 10 percent by weight of thetotal composition, wherein said propellant is a C₃ to C₈ hydrocarbon oflinear or branched configuration.
 12. The composition of claim 11,further comprising a taste mask and/or flavoring agent in an amountbetween 0.05 and 10 percent by weight of the total composition.
 13. Thecomposition of claim 12, wherein the polar solvent is present in anamount between 20 and 97 percent by weight of the total composition, thezolpidem or a pharmaceutically acceptable salt thereof is present in anamount between 0.1 and 15 percent by weight of the total composition,the propellant is present in an amount between 2 and 5 percent by weightof the composition, and the taste mask and/or flavoring agent is presentin an amount between 0.1 and 5 percent by weight of the totalcomposition.
 14. The composition of claim 13, wherein the polar solventis present in an amount between 25 and 97 percent by weight of the totalcomposition, the zolpidem or a pharmaceutically acceptable salt thereofis present in an amount between 0.2 and 25 percent by weight of thetotal composition, the propellant is present in an amount between 2 and4 percent by weight of the composition, and taste mask and/or flavoringagent is present in an amount between 0.1 and 2.5 percent by weight ofthe total composition.
 15. The composition of claim 11, wherein thepolar solvent is selected from the group consisting ofpolyethyleneglycols having a molecular weight between 400 and 1000, C₂to C₈ mono- and poly-alcohols, and C₇ to C₁₈ alcohols of linear orbranched configuration.
 16. The composition of claim 15, wherein thepolar solvent comprises polyethylene glycol.
 17. The composition ofclaim 15, wherein the polar solvent comprises ethanol.
 18. Thecomposition of claim 12, wherein the flavoring agent is selected fromthe group consisting of synthetic or natural oil of peppermint, oil ofspearmint, citrus oil, fruit flavors, sweeteners, and mixtures thereof.19. The composition of claim 11, wherein the propellant is selected fromthe group consisting of propane, N-butane, iso-butane, N-pentane,iso-pentane, neo-pentane, and mixtures thereof.
 20. A method ofadministering zolpidem or a pharmaceutically acceptable salt thereof toa mammal, comprising spraying the oral mucosa of the mammal with thecomposition of claim
 11. 21. The method of claim 20, wherein the amountof the spray is predetermined.
 22. A propellant free buccal spraycomposition for transmucosal administration of zolpidem or apharmaceutically acceptable salt thereof comprising: zolpidem or apharmaceutically acceptable salt thereof in an amount between 0.005 and55 percent by weight of the total composition; and a non-polar solventin an amount between 30 and 99 percent by weight of the totalcomposition.
 23. The composition of claim 22, further comprising a tastemask and/or flavoring agent in an amount between 0.1 and 10 percent byweight of the total composition.
 24. The composition of claim 23,wherein the flavoring agent is selected from the group consisting ofsynthetic or natural oil of peppermint, oil of spearmint, citrus oil,fruit flavors, sweeteners, and mixtures thereof.
 25. The composition ofclaim 22, wherein the solvent is selected from the group consisting of(C₂-C₂₄) fatty acid (C₂-C₆) esters, C₇-C₁₈ hydrocarbons of linear orbranched configuration, C₂-C₆ alkanoyl esters, and triglycerides ofC₂-C₆ carboxylic acids.
 26. The composition of claim 25, wherein thesolvent is a triglyceride.
 27. A method of administering zolpidem or apharmaceutically acceptable salt thereof to a mammal, comprisingspraying the oral mucosa of the mammal with the composition of claim 22.28. The method of claim 27, wherein the amount of the spray ispredetermined.
 29. A buccal spray composition for transmucosaladministration of zolpidem or a pharmaceutically acceptable salt thereofcomprising: zolpidem or a pharmaceutically acceptable salt thereof in anamount between 0.05 and 50 percent by weight of the total composition;and a non-polar solvent in an amount between 19 and 85 percent by weightof the total composition; and a propellant in an amount between 5 and 80percent by weight of the total composition, wherein said propellant is aC₃ to C₈ hydrocarbon of linear or brancehed configuration.
 30. Thecomposition of claim 29, further comprising a taste mask and/orflavoring agent in an amount of between 0.1 and 10 percent by weight ofthe total composition.
 31. The composition of claim 30, wherein theflavoring agent is selected from the group consisting of synthetic ornatural oil of peppermint, oil of spearmint, citrus oil, fruit flavors,sweeteners, and mixtures thereof.
 32. A buccal spray composition fortransmucosal administration of zolpidem or a pharmaceutically acceptablesalt thereof comprising: zolpidem or a pharmaceutically acceptable saltthereof in an amount between 0.01 and 40 percent by weight of the totalcomposition; a non-polar solvent in an amount between 25 and 89 percentby weight of the total composition; a propellant in an amount between 10and 70 percent by weight of the total composition, wherein saidpropellant is a C₃ to C₈ hydrocarbon of linear or brancehedconfiguration; and a taste mask and/or flavoring agent is present in anamount between 1 and 8 percent by weight of the total composition. 33.The composition of claim 32, wherein the propellant is present in anamount between 20 and 70 percent by weight of the total composition, thenon-polar solvent is present in an amount between 25 and 75 percent byweight of the total composition, the zolpidem or a pharmaceuticallyacceptable salt thereof is present in an amount from between 0.25 and 35percent by weight of the total composition, and the taste mask and/orflavoring agent is present in an amount between 2 and 7.5 percent byweight of the total composition.
 34. The composition of claim 29,wherein the propellant is selected from the group consisting of propane,n-butane, iso-butane, n-pentane, iso-pentane, neo-pentane, and mixturesthereof.
 35. The composition of claim 34, wherein the propellant isn-butane or iso-butane and has a water content of not more than 0.2percent and a concentration of oxidizing agents, reducing agents, Lewisacids, and Lewis bases of less than 0.1 percent.
 36. The composition ofclaim 29, wherein the solvent is selected from the group consisting of(C₂-C₂₄) fatty acid (C₂-C₆) esters, C₇-C₁₈ hydrocarbons of linear orbranched configuration, C₂-C₆ alkanoyl esters, and triglycerides ofC₂-C₆ carboxylic acids.
 37. The composition of claim 36, wherein thesolvent is a triglyceride.
 38. A method of administering zolpidem or apharmaceutically acceptable salt thereof to a mammal, comprisingspraying the oral mucosa of the mammal with the composition of claim 29.39. The method of claim 38, wherein the amount of the spray ispredetermined.
 40. A buccal spray composition for transmucosaladministration of zolpidem or a pharmaceutically acceptable salt thereofcomprising: zolpidem or a pharmaceutically acceptable salt thereof in anamount between 0.2 and 10 percent by weight of the total composition;and a polar solvent comprising propylene glycol and ethanol in an amountbetween 50 and 99 percent by weight of the total composition.
 41. Apropellant free buccal spray composition for transmucosal administrationof zolpidem or a pharmaceutically acceptable salt thereof comprising:zolpidem or a pharmaceutically acceptable salt thereof in an amount ofbetween 0.001 and 60 percent by weight of the total composition; and amixture of a polar solvent and a non-polar solvent in an amount ofbetween 30 and 99.69 percent by weight of the total composition, whereinthe ratio of the polar solvent to the non-polar solvent ranges from 1:99to 99:1.
 42. The composition of claim 40, further comprising a tastemask and/or flavoring agent in an amount of between 0.1 and 10 percentby weight of the total composition.
 43. The composition of claim 42,wherein the polar solvent is present in an amount between 37 and 98percent by weight of the total composition, the zolpidem or apharmaceutically acceptable salt thereof is present in an amount between0.005 and 55 percent by weight of the total composition, and the tastemask and/or flavoring agent is present in an amount between 0.5 and 8percent by weight of the total composition.
 44. The composition of claim43, wherein the polar solvent is present in an amount between 60 and 97percent by weight of the total composition, the zolpidem or apharmaceutically acceptable salt thereof is present in an amount between0.01 and 40 percent by weight of the total composition, and the tastemask and/or flavoring agent is present in an amount between 0.75 and 7.5percent by weight of the total composition.
 45. The composition of claim41, wherein the polar solvent is selected from the group consisting ofpolyethylene glycols having a molecular weight between 400 and 1000, C₂to C₈ mono- and poly-alcohols, and C₇ to C₁₈ alcohols of linear orbranched configuration and the non-polar solvent is selected from thegroup consisting of (C₂-C₂₄) fatty acid (C₂-C₆) esters, C₇-C₁₈hydrocarbons of linear or branched configuration, C₂-C₆ alkanoyl esters,and triglycerides of C₂-C₆ carboxylic acids.
 46. The composition ofclaim 42, wherein the flavoring agent is selected from the groupconsisting of synthetic or natural oil of peppermint, oil of spearmint,citrus oil, fruit flavors, sweeteners, and mixtures thereof.
 47. Amethod of administering zolpidem or a pharmaceutically acceptable; saltthereof to a mammal, comprising spraying the oral mucosa of the mammalwith the composition of claim
 41. 48. The method of claim 47, whereinthe amount of the spray is predetermined.
 49. A buccal spray compositionfor transmucosal administration of zolpidem or a pharmaceuticallyacceptable salt thereof comprising: zolpidem or a pharmaceuticallyacceptable salt thereof in an amount between 0.05 and 50 percent byweight of the total composition; a mixture of a polar solvent and anon-polar solvent in an amount between 10 and 97 percent by weight ofthe total composition, wherein the ratio of the polar solvent to thenon-polar solvent ranges from 1:99 to 99:1; and a propellant in anamount between 5 and 80 percent by weight of the total composition,wherein said propellant is a C₃ to C₈ hydrocarbon of linear or branchedconfiguration.
 50. The composition of claim 49, further comprising ataste mask and/or flavoring agent is present in an amount between 0.01and 10 percent by weight of the total composition.
 51. The compositionof claim 50, wherein the propellant is present in an amount between 10and 70 percent by weight of the total composition, the solvent ispresent in an amount between 20 and 97 percent by weight of the totalcomposition, the zolpidem or a pharmaceutically acceptable salt thereofis present in an amount from between 0.1 and 40 percent by weight of thetotal composition, and the taste mask and/or flavoring agent is presentin an amount between 1 and 8 percent by weight of the total composition.52. The composition of claim 49, wherein the propellant is selected fromthe group consisting of propane, n-butane, iso-butane, n-pentane,iso-pentane, neo-pentane, and mixtures thereof.
 53. The composition ofclaim 52, wherein the propellant is n-butane or iso-butane and has awater content of not more than 0.2 percent and a concentration ofoxidizing agents, reducing agents, Lewis acids, and Lewis bases of lessthan 0.1 percent.
 54. The composition of claim 49, wherein the polarsolvent is selected from the group consisting of polyethylene glycolshaving a molecular weight between 400 and 1000, C₂ to C₈ mono- andpoly-alcohols, and C₇ to C₁₈ alcohols of linear or branchedconfiguration and the non-polar solvent is selected from the groupconsisting of (C₂-C₂₄) fatty acid (C₂-C₆) esters, C₇-C₁₈ hydrocarbons oflinear or branched configuration, C₂-C₆ alkanoyl esters, andtriglycerides of C₂-C₆ carboxylic acids.
 55. A method of administeringzolpidem or a pharmaceutically acceptable salt thereof to a mammal,comprising spraying the oral mucosa of the mammal with the compositionof claim
 49. 56. The method of claim 55, wherein the amount of the sprayis predetermined.
 57. A method of treating insomnia in a patient,comprising spraying the oral mucosa of the patient with atherapeutically effective amount of the buccal spray of claim
 1. 58. Amethod of treating insomnia in a patient, comprising spraying the oralmucosa of the patient with a therapeutically effective amount of thebuccal spray of claim
 11. 59. A method of treating insomnia in apatient, comprising spraying the oral mucosa of the patient with atherapeutically effective amount of the buccal spray of claim
 22. 60. Amethod of treating insomnia in a patient, comprising spraying the oralmucosa of the patient with a therapeutically effective amount of thebuccal spray of claim
 29. 61. A method of treating insomnia in apatient, comprising spraying the oral mucosa of the patient with atherapeutically effective amount of the buccal spray of claim
 41. 62. Amethod of treating insomnia in a patient, comprising spraying the oralmucosa of the patient with a therapeutically effective amount of thebuccal spray of claim 49.